PHARMACOKI

ETICS·THERAPEUTI S

Clin. Pharmacokinet. 21 (6): 479-493, 1991 0312-5963/91/0012-0479/$07.50/0 © Adis International Limited. All rights reserved. CPK187

Pharmacokinetic Justification of Antiprotozoal Therapy A US Perspective Jonathan D. Berman and Lawrence Fleckenstein Walter Reed Army Institute of Research, Washington, DC, USA

Contents 479

Summary

Summary I. Protozoal Diseases 1.1 Amoebiasis 1.2 Giardiasis 1.3 Leishmaniasis 1.4 Plasmodial Infections (Malaria) 1.5 Pneumocystis carinii Pneumonia 1.6 Toxoplasmosis I. 7 African Trypanosomiasis 1.8 American Trypanosomiasis 2. Antiprotozoal Chemotherapeutic Agents 2.1 Agents Active against Amoebiasis 2.2 Agents Active against Giardiasis 2.3 Agents Active against Leishmaniasis 2.4 Agents Active against Malaria 2.5 Agents Active against Pneumocystis carinii and Toxoplasmosis 2.6 Agents Active against Trypanosomiasis 3. Comments

Infections with parasitic protozoa have always been problems for the developing world and are becoming of greater importance to the developed world in this age of easy international travel. The major human protozoal diseases are summarised with an emphasis on their presentation in normal hosts and in immunocompromised individuals and current US drug treatment recommendations are discussed. Present anti protozoal regimens are based either on a pharmacokinetic rationale or on clinical trial and error. Regimens based on trial and error include amphotericin B against leishmaniasis and arsenic against African trypanosomiasis. Regimens which are to some extent driven by pharmacokinetic or biochemical considerations include paromomycin and metronidazole against amoebiasis, sodium stibogluconate against leishmaniasis, halofantrine and mefloquine against malaria, dihydrofolate reductase (DHFR) inhibitors against Pneumocystis carinii and toxoplasmosis and aerosolised pentamidine against P. carinii pneumonia. The majority of pharmacokinetic studies have been performed only on agents which have some therapeutic activity against other diseases of the developed world. Despite the trend toward rational treatment regimens, no studies have been performed that permit optimisation of anti protozoal treatment regimens on the basis of clinical conditions such as renal failure.

480

Parasitic diseases are central to the health concerns of developing nations and as the twentieth century draws to a close, they are also being recognised as medically important to the developed world. Large numbers of people are travelling or changing residence between the developed and developing nations. Some normally commensal parasites are significant causes of mortality in patients with immune deficiencies and the acquired immune deficiency syndrome (AIDS). The interest in parasitic diseases in both the developed and developing worlds is leading to increased clinical investigation of these diseases and of their chemotherapy. We review the pharmacokinetic rationale for antiprotozoal chemotherapy. Ultimately, understanding the pharmacokinetic basis of therapy will permit modification of chemotherapy in patients with specific clinical problems such as cardiac or renal failure. However, the historic lack of study of antiparasitic therapy makes it difficult to justify the details of many anti protozoal regimens and we are not aware of any studies dealing specifically with optimisation of therapy based on pharmacokinetics, even for the more recently developed agents such as mefloquine. The major protozoal diseases with which clinicians should be familiar are those due to Entamoeba histolytica, Giardia lamblia, Leishmania spp., Plasmodium spp. (malaria), Pneumocystis carinii, Toxoplasma gondii, Trypanosoma gambiense, Trypanosoma rhodensiense and Trypanosoma cruzi. A discussion of cryptosporidiosis is omitted because there is no established therapy for this disease. For each type of organism, a brief discussion of the associated clinical syndromes is followed by a summary of the drug therapy recommended in the US. Dosage recommendations, indications and common adverse effects of chemotherapeutic agents are listed in table I. Since this is a review of drug pharmacokinetics rather than of the treatment recommendations themselves, we accepted the consensus represented by Abramowitz (1988), updated by recent US recommendations on malaria (Editorial 1991; Lobel et al. 1991). The anti protozoal agents are discussed individ-

Clin. Pharrnacokinet. 21 (6) 1991

ually to emphasise pharmacokinetic considerations which may lead to their recommended dosage regimens.

1. Protozoal Diseases 1.1 Amoebiasis In the life cycle of E. histolytica, encysted organisms are excreted by I host, survive a variety of environmental conditions and are ingested in contaminated water or food by a new host. Direct inoculation of the bowel may also occur during anal sexual practices. Most infected persons are asymptomatic. After an incubation period of I week, symptomatic patients may experience either colicky abdominal pain and loose stools or frequent bloody stools, fever and abdominal tenderness. In some patients bowel perforation and peritonitis may occur. Acute intestinal disease may progress to chronic disease characterised by abdominal pain, weight loss and intermittent diarrhoea. Patients who receive the organisms per rectum may have inflammation and ulceration of the distal colon. Hepatic amoebiasis (with right upper quadrant abdominal pain, fever and weight loss) may result after either asymptomatic or symptomatic intestinal disease and can occur days to years after the initial infection. If amoebiasis is limited to the intestinal lumen, diagnosis is made by finding the organism in the stool. Invasive intestinal and liver disease is accompanied by elevated antiamoebic serology. Recommended treatment is based on the degree of tissue involvement. Patients with mild intestinal symptoms that signify only luminal involvement and asymptomatic patients passing amoebic cysts should receive oral diloxanide, iodoquinol or paromomycin. Patients with invasive intestinal or hepatic disease should receive oral metronidazole. 1.2 Giardiasis

Giardia lamblia is spread by ingestion of contaminated food or water. Although most infected persons are asymptomatic, symptoms may begin I to 3 weeks after ingestion when the organisms ap-

Antiprotozoal Therapy

481

Table I. Dosage recommendations, indications and common adverse effects of anti protozoal chemotherapeutic agents [data from Abramowicz (1988) unless otherwise noted] Drug

Indication

Dosage

Adverse events

Amphotericin B Antimony (V)

Leishmaniasis Leishmaniasis

Kidney (potassium, BUN) Cardiac (repolarisation)

Arsenic (III) (melarsoprol) Chloroquine

African trypanosomiasis

Difluoromethylornithine Diloxanide Doxycycline

Malaria Px West African trypanosomiasis Amoebiasis (luminal) Malaria Px

1 mg/kg/d x 3Od, IV 20 mg/kg/d x 20-3Od, IV or 1M 3 IV injections per week for 4 wks, total of 37.Smg 600mg base, then 300mg q6hx3PO 300mg base/w PO 100 mg/kg q6H IV for 2 wks SOOmg tid x 10d 100mg od PO

Furazolidone Halofantrine lodoquinol Mefloquine

Giardiasis Malaria Tx Amoebiasis (luminal) Malaria Tx

100mg qid x 7-10d, PO SOOmg q6h x 3, PO 6S0mg tid x 20d, PO 12S0mg once PO

Malaria Px Amoebiasis (extraintestinal) Giardiasis American trypanosomiasis

2S0mg/w PO 7S0mg tid x 10d PO

Amoebiasis (luminal) Leishmaniasis P. carinii Tx P. carinii Px Malaria radical cure Malaria Px

9 mg/kg tid x 7d PO 4 mg/kg/d x 14d 1M 4 mg/kg/d x 14d 1M 4 mg/kg q 4wks ae 1Smg base/d x 14d PO 200mg od PO

Malaria Tx toxoplasmosis Malaria Tx

Metronidazole

Nifurtimox

Paromomycin Pentamidine

Primaquine Proguanil Pyrimethamine

Malaria Tx

2S0mg tid x Sd PO 2-2.S mg/kg qid x 90-120 d PO

Quinidine (gluconate) Quinine

Malaria Tx

Quinacrine

Giardiasis

2Smg bid x 3d PO 2Smg bid x ?d PO 10 mg/kg, then 0.02 mg/ kg/min IV 6S0mg tid x 3d PO 600mg tid IV 100mg tid x Sd PO

Spiramycin Sulfadiazine Sulfamethoxazole

Toxoplasmosis Malaria Tx Toxoplasmosis P. carinii

2-4 g/d x 4 wks SOOmg qid x Sd, PO 2-4 g/d x ?d PO SO mg/kg bid x 14-21d PO

Suramin

African trypanosomiasis

Trimethoprim

P. carinii

1000mg on days 1, 3, 7, 14,21 IV 10 mg/kg bid x 14-21d PO

CNS (convulsions)

Reference

Wellde et al. (1989)

GI (nausea, vomiting) Skin (pruritis) Haematological (platelets) Van Nieuwenhove et al. (198S) GI (diarrhoea) GI (flatulence) GI (nausea, vomiting) Eye (photosensitivity) GI (nausea, vomiting) GI Skin (rash) CNS (dizziness) GI (nausea, vomiting, diarrhoea) Editorial (1990) GI (nausea)

GI (vomiting) CNS (encephalitis motor disturbances) GI Endocrine (glucose imbalance) Methaemoglobinaemia GI (vomiting, abdominal pain) Haematological (pancytopenia) Cardiac (arrhythmia) CNS (tinnitus, nausea) CNS (tinnitus, headache, nausea, vision) CNS (dizziness, headache) GI Skin (rash)

Editorial (1991)

Skin (rash, urticaria) GI (nausea, vomiting) Chills, rigors GI (nausea, vomiting)

Abbreviations: V = pentavalent; III = trivalent; Tx = treatment; Px = prophylaxis; IV = intravenous; 1M = intramuscular; PO = oral; d = days; od = once daily; wks = weeks; ae = aerosol; q4 wks = once every 4 weeks; qid = 4 times daily; bid = twice daily; tid = 3 times daily; q6h = every 6 hours; GI = gastrointestinal; CNS = central nervous system; BUN = blood urea nitrogen.

482

Clin. Pharmacokinet. 21 (6) 1991

pear in the stool. Flatulence, abdominal cramps, nausea and foul-smelling diarrhoea are common. Symptoms may remit spontaneously after 2 to 6 weeks or loose, foul-smelling stools and epigastric pain may continue for months. Diagnosis is made by visualising the organisms in faecal material or duodenal fluid. Treatment with the oral agents furazolidone, quinacrine or metronidazole cures 80 to 90% of patients. 1.3 Leishmaniasis Leishmania spp. are injected into the skin by the bite of the sandfly. The organisms then locate either in the macrophages of the skin, causing cutaneous disease, or in the macrophages of the liver, spleen and bone marrow, causing visceral disease. Spread of cutaneous organisms to the oronasal mucosa gives rise to mucosal disease. Although cutaneous disease spontaneously cures in months to years, the disease should be treated because oflocal morbidity and the possibility of mucosal spread. Disease of the nasal mucosa progresses indolently over several years to ablate the nasal cartilage; laryngeal-pharyngeal disease may progress to suffocation. Visceral disease progresses more rapidly (within months) to cause death by bone marrow failure. Diagnosis is made by visualising the organism in specimens from lesions. All forms of leishmaniasis other than mild cutaneous disease may be treated with parenteral pentavalent antimony in the form of sodium stibogluconate ('Pentostam') or meglumine antimonate ('Glucantime'). When antimony treatment fails, treatment with other parenteral agents such as pentamidine or amphotericin B is recommended.

1.4 Plasmodial Infections (Malaria) Malaria is initiated by the bite of the female anopheline mosquito, during which plasmodia sporozoites are injected into the blood stream. Within lh, the sporozoites invade liver parenchymal cells within which they transform into merozoites and multiply. nie multiplying organisms usually rupture the liver cells within I to 3 weeks, invade

erythrocytes and, after multiplication, rupture the red cells. Liberated parasites invade other red cells to repeat the erythrocyte cycle. Symptoms are related to parasitisation and rupture of erythrocytes. Parasitised red cells are sequestered by the spleen and cause splenomegaly. Red cells parasitised with Plasmodium Jalciparum adhere to and occlude vascular endothelium. Erythrocytic rupture releases endogenous pyrogens and causes anaemia and haemoglobinuria. Immune reactions stimulated by parasitised erythrocytes may also occur. The classic malarial paroxysm consists of a cold phase (vasoconstriction) followed by a hot phase of high body temperature of about 41°C (lOYF), vasodilation and abdominal pain, followed by defervescence. Initially, parasites may leave the liver asynchronously to invade and rupture red cells and the periodicity of symptoms described in classic cases may not be seen in the present day if medical attention is rapidly sought, prior to synchronous rupture of hepatocytes and invasion and subsequent rupture of red cells. The diagnosis of malarial infection is made by visualising P. Jalciparum, Plasmodium vi vax, Plasmodium ovale or Plasmodium malariae within red cells on a blood smear. Malarial prophylaxis is with chloroquine in areas where there is chloroquine sensitivity, such as the Middle East and Central America (Editorial 1990). Because many P. Jalciparum strains are now resistant to chloroquine in most parts of Southeast Asia, India, Africa and South America, alternatives to chloroquine are essential and include the dihydrofolate reductase (DHFR) inhibitor proguanil (administered daily in addition to chloroquine), daily doxycycline (in addition to chloroquine) or weekly mefloquine. Because each of these agents has disadvantages (doxycycline is contraindicated in children under 8 years and pregnant women; resistance to DHFR inhibitors occurs; mefloquine resistance and its toxicity are not well delineated) there is no simple prophylactic choice in the regions of the world in which chloroquine resistance occurs. Treatment of malaria due to non-Po Jalciparum organisms or to chloroquine-sensitive P. Jalciparum is with oral chloroquine (Panisko & Keystone

483

Antiprotozoal Therapy

1990). Chloroquine-resistant P. falciparum may be treated with quinine plus the DHFR inhibitor pyrimethamine plus the dihydropteroate synthetase (DHPS) inhibitor sulfadiazine, or with quinine, tetracycline, mefloquine or halofantrine. For severe P. falciparum infections, treatment is initiated parenterally. As of April 1991, the US Centers for Disease Control (CDC) recommend parenteral quinidine, rather than quinine. Because P. vivax and P. ovale may not exit the liver for months or years, radical cure of the exoerythrocytic forms is required and is accomplished with primaquine. Amodiaquine, a 4-aminoquinoline antimalarial drug, is superior to chloroquine against some strains of chloroquine-resistant P. falciparum. The drug is rapidly and extensively metabolised to desethylamodiaquine, an active metabolite which is probably responsible for most of the therapeutic effect (Winstanley et al. 1990). Amodiaquine treatment carries a significant risk of agranulocytosis and hepatitis. Since this agent is effective and inexpensive and because no cases of serious toxicity have been reported during treatment of acute malaria, amodiaquine is still used in some countries. Nevertheless, the drug is not generally recommended in the developed world and we do not recommend it. Prophylaxis and treatment of malaria is complicated by the dynamic nature of drug resistance to chloroquine and other agents. Patterns of resistance may reflect the patterns of drug use, which differ in endemic areas of the world. Recognition of drug resistance requires timely surveillance of clinical and in vitro data. 1.5 Pneumocystis carinii Pneumonia P. carinii is reported, on the basis of 16s rRNA sequences, to be a fungus, but is discussed in this review of antiprotozoal therapy because it is treated with antiprotozoal drugs. The infective stage of the organism is unknown (Davey & Masur 1990). Simply being immunosuppressed is sufficient for humans and laboratory mammals to become infected. Almost all symptomatic infection is manifested by pneumonia. Patients with cancer

typically have rapidly progressive hypoxia, whereas patients with AIDS will manifest a prolonged development of dyspnoea, low-grade fever, cough and fatigue. The diagnosis is made by visualising the organisms in stained specimens obtained by bronchoalveolar lavage or transbronchial biopsy. P. carinii pneumonia is treated with oral or intravenous cotrimoxazole (trimethoprim plus sulfamethoxazole). Patients intolerant of cotrimoxazole should receive intramuscular pentamidine. Since virtually all patients with AIDS who have CD4 counts of less than 200 cells/mm 3 will develop P. carinii infection unless other infections develop first, prophylaxis against P. carinii has recently been recommended. Two prophylactic regimens are oral cotrimoxazole or aerosolised pentamidine every 4 weeks. For both treatment and prophylaxis, inhibitors of DHFR other than trimethoprim and inhibitors of DHPS other than sulfamethoxazole are being tested. 1.6 Toxoplasmosis Humans are infected by ingestion of the oocysts/ sporozoites excreted by felines. The sporozoites multiply and disseminate to all organs and tissues. In the immunocompetent host, toxoplasmosis is generally asymptomatic, although lymphadenopathy or retinitis occur occasionally. Toxoplasma gondii may cross the placenta to the immunologically immature fetus. Fetuses infected early in gestation have a high risk of neurological defects including retinitis, convulsions and retardation in addition to hepatosplenomegaly. In immunocompromised patients with cancer or AIDS, reactivation of previously latent toxoplasmosis may result in symptoms of encephalitis. A wide range of complaints such as headache, disorientation or focal neurological impairment may be seen. Diagnosis is by serology, sometimes with confirmation by visualising organisms in tissue specimens from patients with a compatible clinical presentation. Symptomatic toxoplasmosis is treated with the DHFR inhibitor pyrimethamine and the DHPS inhibitor sulfadiazine or alternatively with spiramycin.

484

1. 7 African Trypanosomiasis African trypanosomiasis is initiated by the bite of the tsetse fly. The early phase of disease due to T. gambiense, generally acquired in West Africa, begins approximately 1 year after infection; that due to T. rhodesiense, acquired in East Africa, begins a few days after infection. In both diseases, the early phase is characterised by tachycardia, intermittent fever, subtle neurological signs and, in patients with T. gambiense disease, lymphadenopathy. Gambiense disease progresses slowly and rhodesiense disease progresses rapidly to the late phase of neurological involvement that gives 'sleeping sickness' its name. Patients are characteristically somnolent with Parkinsonian facies. However, periods of manic hyperactivity, irritability and involuntary movements may be seen and personality changes are common. Diagnosis is made by visualising the organisms in cerebrospinal fluid (CSF), lymph node fluid or blood. Intravenous suramin is used to treat early stage symptoms when the CSF is normal. Late stage disease is treated with intravenous organic arsenic in the form of melarsoprol ('Mel B'). It is important in East African disease to verifY the lack of central nervous system (CNS) involvement by examining the CSF. Patients who, on merely clinical grounds, are thought not to have CNS involvement and are then treated with suramin have a high (49%) rate of neurological relapse (Wellde et al. 1989). Recently, the ornithine decarboxylase inhibitor difluoromethylornithine has been approved for the treatment of West African disease including disease with CNS involvement. 1.8 American Trypanosomiasis Patients are inoculated with T. cruzi by the bite of riduviid bugs. Acute disease characterised by fever and oedema of the face and lower extremities, and reticuloendothelial enlargement, occurs in a small percentage of patients within weeks after infection. A few patients with acute disease will experience myocarditis (which can lead to death via congestive heart failure) or meningioencephalitis.

Clin. Pharmacokinet. 21 (6) 1991

Except for the rare fatal cases of heart failure, patients with acute disease recover spontaneously over a period of 2 to 3 weeks. Acute disease is at least partially caused by motile parasites which can be visualised in blood. Chronic Chagas' disease, which presumably occurs due to an immune reaction to intracellular organisms, appears years to decades after initial infection and results in cardiac involvement (arrhythmias, congestive heart failure) and gastrointestinal disease (megaoesophagus, megacolon). The diagnosis of acute disease is made by visualising parasites in fresh blood. Since parasitaemia is uncommon, chronic disease is generally diagnosed by the appearance of antibodies to T. cruzi. Specific treatment is only available for acute disease. The treatment is oral nifurtimox for 90 to 120 days.

2. Antiprotozoal Chemotherapeutic Agents Pharmacokinetic data on anti protozoal chemotherapeutic agents are listed in table II. Omissions from table II signify where data are unobtainable. Where use of these data has led to therapeutic recommendations, these are summarised below. The agents are grouped by the diseases against which they are used. 2.1 Agents Active Against Amoebiasis

2.1.1 Diloxanide, /odoquinol, Paromomycin and Metronidazole The pharmacokinetics of diloxanide, iodoquinol and paromomycin are sparsely reported. 10doquinol is a poorly soluble antiamoebic quinoline introduced into clinical practice in the 1930s and 1940s. Its absorption after oral administration and the reasons for its low bioavailability have not been investigated. Its poor bioavailability makes it useful for the treatment of purely luminal disease. Paromomycin is an aminoglycoside which, like other aminoglycosides, is not absorbed via the gastrointestinal tract, but unlike other aminoglycosides, is active against several protozoa (E. histolytica,

Antiprotozoai Therapy

485

Table II. Pharmacokinetic data [from Goodman & Gilman (1985) unless otherwise noted] Drug

tv.a

Amphotericin B

1-2d (a) 15d 2h (a) 76h

Antimony (V)

(n (n

Arsenic (III) [Mel B] Chloroquine Difluoromethylornithine Diloxanide Doxycycline Furazolidone Halofantrine lodoquinol Mefloquine

21d

Metronidazole

8h

4 0.22

9d 3h

165 0.34

16h

0.75

3-5d

Nifurtimox

",4h

Paromomycin Pentamidine

NA 9h

Primaquine

Vd (L/kg)

5h

100b 20'

Cmax (mg/L)

1 (50mg)

Pb ("/0)

fa ("/0)

>90

3

20 (20 mg/kg)

high

>90

0.25 (25 mg/kg) 15 (20 mg/kg)

61

50 83

1-3 (200mg)

88

0.6 1.2 (1.0g)

6.9 (400mg)

41 Low

CL (ml/min/kg)

0.43

2.0

Pharmacokinetic justification of antiprotozoal therapy. A US perspective.

Infections with parasitic protozoa have always been problems for the developing world and are becoming of greater importance to the developed world in...
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